PROJECTSUMMARY The2015UNAIDSreportestimatesthatover35millionpeopleareinfectedwithHIV.Despitethelack ofasterilizingcure,antiretroviraldrugtherapies(ART)effectivelysuppressviralreplicationininfected individuals.However,only17millioninfectedindividualshaveaccesstoART.Additionally,ARTisa life-longtherapythatrequiresdailyadministrationandisassociatedwitharangeofunwantedside effects.Broadlyneutralizingantibodies(bNAbs)maybeabletosupplementorreplaceART.Several suchantibodieshavealreadyshownpromiseinhumanclinicaltrials,whereasingledosecandecrease viremiainHIV-1infectedindividuals.However,viralreboundoccursrapidlyduringtreatmentasthe bNAbconcentrationdecreasesandresistantvariantsareselected.Adeno-associatedvirus(AAV) vectorscanexpressbNAbsforyearsatconcentrationscapableoflimitingviralevolutionand maintainingviralsuppression.However,weandothergroupshaveshowntheemergenceofanti-drug antibodies(ADA)toexpressedbNAbsthatcanlimittheirexpression.InthisK99/R00proposal,Iwill addressthreekeyquestionsassociatedwiththeuseofAAV-deliveredbNAbsinafunctionalcure.1) WhichbNAbshavebiophysicalandneutralizationpropertiesconsistentwithsuppressingan establishedinfection?2)CanvectorandAAVcapsidoptimizationincreasebNAbexpressionandhelp limitthehostADAresponse?3)CanAAV-deliveredbNAbssuppressanestablishedSHIVinfectionin rhesusmacaques,obviatingtheneedforART?Byansweringthesequestions,wewilldeterminehow besttouseAAVvectorstotreatanAAVinfection,andprovideinsightforinvestigatorsusingAAVin otherclinicalcontexts.MyresearchwithAAVandHIV-1systemsandmydevelopmentofnon-human primateprojectsasaRuthL.KirschsteinFellowhaveprovidedmewiththetrainingnecessaryto completetheseaims.TSRIprovidesanoutstandingresearchenvironmentforcollaborativescience, especiallyintheHIVfield.Moreover,IwillattendcoursesofferedatTSRIandColdSpringHarborthat willprovidefurthertrainingonbecominganindependentinvestigator.Mymentor,Dr.Farzan,along withmyScientificAdvisoryCommitteeconsistingofDrs.RonDesrosiers,SusanaValenteandHyeryun Choe,arecommittedtoprovidingmewithanexcellenttrainingindevelopingmyresearchgoalsand improvingmygrantwritingskillsforfutureR01submissions.TheskillsIacquireduringthetraining phasewillserveasafoundationformyownresearchprogramduringtheindependentphase,withthe specificgoalsofdevelopingnewgene-therapyvectorsandapplyingthesevectorstohumandiseases.